CCK is a gastrointestinal hormone of 33 amino acids which is utilized by the body in the cascade of events which are part of hunger, eating, digestion and satiety. Other such hormones include gastrin and secretin. The presence of acid, fat and protein breakdown products or any irritating factor in the upper small intestine causes the release of secretin and CCK. Both of these are important for control of pancreatic secretion and CCK is essential for emptying of the gallbladder, see Chapter 64, entitled "Secretory Functions of the Alimentary Tract" in A.C. Guyton's Textbook of Medical Physiology, W. B. Saunders, 1986 Philadelphia.
CCK has a variety of regulatory roles in the periphery including gallbladder contraction and pancreatic enzyme secretion (V. Mutt in "Gastrointestinal Hormones", G. B. J. Glass, ed, Raven Press, New York, 1980 pp. 169; J. A. Williams, Biomed. Res., 1982 pp. 3:107), inhibition of gastric emptying and suppression of food intake. CCK and its fragments are believed to play an important role in appetite regulation and satiety (Della-Fera, Science, 1979 pp. 206:471; Saito et al., Nature, 1981 pp. 289:599; and Smith "Eating and its Disorders", A. J. Stunkard and E. Stellar, eds., Raven Press, New York, 1984 p. 67) and recently, patients with bulimia were shown to have lower than normal CCK levels in their plasma (Geracioti et al., New England Journal of Medicine, 1988 pp. 319:683).
CCK in the brain has been suggested to have a role in schizophrenia (N. P. V. Nair et al, Prog. Brain Res, 1986 pp. 65:237), memory and cognition (S. Itoh and H. Lal, Drug Dev. Res., 1990, pp. 21:257), and CCK antagonists have been suggested to be potentially useful in drug abuse therapy (B. Costall et al. in "Proceedings of the Cambridge Symposia, The Neurological Basis of Anxiety," Robinson College, Cambridge, U.K., Sep. 7 and 8, 1990).
Two sub-types of the CCK receptor have been identified. Type-A CCK receptors, commonly referred to as the "peripheral-type" receptor, are primarily found in the pancreas, gallbladder, ileum, pyloric sphincter and on vagal afferent nerve fibers. Type-A CCK receptors bind CCK-8 with high affinity but have low affinity for desulfated CCK-8 and CCK-4. The brain contains predominantly the Type-B receptors that bind CCK-8, desulfated CCK-8 and CCK-4 with high affinity. Type-A CCK receptors are found in the brain, although in low abundance (D. R. Hill et al., Brain Res, 1988, pp. 454:101-5; D. R. Hill et al., Neurosci Lett., 1988, pp 89:133-9; R. W. Barrett et al., Mol. Pharmacol, 1989, 36:285-90; and D. R., Hill et al., J. Neurosci, 1990, 10:1070, 81), and play an important role there also (V. Dauge et al., Pharmacol Biochem Behav., 1989 33:637-40). Type-A receptor-selective CCK agonists are currently of particular interest as potential anorectic agents because of the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species (Della-Fera et al., Science, 1979, 206:471; K. E. Asin et al., Intl Conference on Obesity., 1990, Abstract p. 40).
Obesity is a major disorder affecting as much as one third of the North American population. Several studies have shown that such individuals are at increased risk in developing cardiovascular disease (hypertension and hypercholesterolemia), diabetes and several types of cancer. The effective treatment of obesity, however, remains a largely unachieved goal. Existing pharmacotherapeutic approaches to weight loss involve the use of amphetamine-based agents such as amphetamine, diethylpropion, mazindol and fenfluramine which act directly on the CNS to lower food intake by modulating dopaminergic, adrenergic and/or serotonergic mechanisms. Although weight loss can be achieved with such agents, their use is restricted due to CNS side-effects, potential addiction liability and the production of tolerance to their actions, with chronic administration leading to potential depression, vestibular disturbances, hallucinations and addiction, as well as interference with the actions other drugs such as MAO inhibitors and antihypertensives. There is also a subpopulation of obese patients that is refractory to present anorectic drug treatments.
Additional roles for CCK in the periphery (body) include stimulation of gall bladder contraction, and inhibition of gastric emptying. CCK in the brain has been suggested to have a role in schizophrenia, memory and cognition and CCK antagonists have been suggested to be useful in drug abuse therapy, all as set forth in the previous citations or in citations therein.
CCK agonists or analogs of CCK-8, a particular biologically active form of CCK, have been published. For example, U.S. Pat. No. 4,490,364, issued Dec. 25, 1984 discloses heptapeptide, octapeptide and nonapeptide analogs of CCK-8 as CCK agonists for stimulating gallbladder contractions, arresting the secretion of gastric acid and treating convulsions.
European Patent Application EP381,340, published Aug. 8, 1990, and European Patent Application EP 268,297, published May 25, 1988, disclose hepta- and octapeptides with sulfate ester groups which are useful for treating obesity.
Orally active CCK-B receptor selective dipeptoid antagonists are described in European Patent 465,537 published Jan. 2, 1991 and by D. C. Horwell et al., in J. Med. Chem., 34, 1991, pp. 404-414. These compounds have weak CCK-A receptor affinity, being &gt;500-fold selective for CCK-B receptors, and are reported to be useful as anti-anxiety and anti-ulcer agents. These compounds also possess weak anorectic activity resulting from their weak affinity for CCK-A receptors. Six related disclosures have been published. PCT WO 92/04348 published March 19, 1992 teaches carboline derivatives useful in treating obesity while cholecystokinin antagonists are described in PCT WO 92/04045 and WO 92/04025. Dipeptoids to treat obesity are taught in PCT WO 92/04322 while pro-drugs to dipeptoids are shown in PCT WO 92/04038. Peptoids for treating obesity are found in PCT WO 92/04320.
CCK antagonists or gastrin receptor antagonists comprising C-terminal fragments of CCK have recently been reported. See Jensen et al., Biochem. Biophys. Acta, 1983, pp. 757-250; Spanarkel, J. Biol. Chem. 1983, pp. 258-6746. Japanese Patent Application 45/1050 to Miyao et al. discloses a tetrapeptide derivative of the carboxy terminal sequence of gastrin (L-Trp-L-Lys-L-Asp-L-PheNH.sub.2) which acts as antagonists of gastrin.
CCK-A receptor selective tetrapeptide agonists are described in the literature as agents to treat gastrointestinal disorders (including gall bladder stasis), CNS disorders and pain as well as appetite regulation, see PCT WO 91/19733 published Dec. 26, 1991, by K. Shiosaki et al., in J. Med. Chem., 33, 1990 pp. 2950-2952 and in PCT WO 90/06937, published Jun. 28, 1990.
The present invention describes CCK-A receptor selective agents which modulate peripheral CCK receptors.